Enhancing anti-tumour T-cell function represents a unique approach for treating cancer. There is considerable evidence that tumour cells ‘escape’ the immune system by induction of an active immune tolerance largely mediated by regulatory T lymphocytes (Tregs; Quezda et al. Immunol Rev 2011; 241:104-118). Therefore, the balance between effector (i.e., direct or indirect eradication of tumour cells) T lymphocytes (Teffs) and tolerogenic (i.e., suppression of Teffs effector function and survival) Tregs appears to be crucial for effective anti-tumour immunotherapy. In other words, an effective anti-tumour immune response can be obtained by enhancing effector function of tumour-specific Teffs and/or by attenuating suppressive function of tumour-specific Tregs. A key receptor that has been shown to mediate these responses is the CD134 (OX40) receptor. (Sugamura, K, Ishii, N, Weinberg, A. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nature Rev Imm 2004; 4: 420-431).
CD134 (also known as OX40, TNFRSF4, and ACT35) is a member of the tumour necrosis factor receptor superfamily. This CD134 surface co-stimulatory receptor is expressed on activated T lymphocytes, and plays an important role in their survival and function. The presence of CD134 expressing T lymphocytes has been demonstrated in various human malignant tumours and in the draining lymph nodes of cancer patients (Ramstad et al. Am J Surg 2000; 179: 400-406; Vetto et al. Am J Surg 1997; 174: 258-265).
In vivo ligation of the mouse CD134 receptor (by either soluble mouse OX40 ligand (OX40L)-immunoglobulin fusion proteins or mouse OX40L mimetics, such as anti-mouse CD134-specific antibodies) in tumour-bearing mice enhances anti-tumour immunity, leads to tumour-free survival in mouse models of various murine malignant tumour cell lines, e.g., lymphoma, melanoma, sarcoma, colon cancer, breast cancer, and glioma (Sugamura et al. Nature Rev Imm 2004; 4: 420-431).
It has been proposed to enhance the immune response of a mammal to an antigen by engaging the OX40R through the use of an OX40R binding agent (WO 99/42585; Weinberg, 2000). Although the document refers generally to OX40-binding agents, the emphasis is on the use of OX40L or parts thereof; the disclosure of anti-OX40 antibodies is in the context of their being equivalent to OX40L. Indeed, when the Weinberg team translated the research to a study with non-human primates, they again deliberately chose an antibody that binds to the OX40L-binding site and generally mimics OX40L.
Al-Shamkhani et al. (Eur J Chem 1996; 26: 1695-1699) used an anti-OX40 antibody called OX86, which did not block OX40L-binding, in order to explore differential expression of OX40 on activated mouse T-cells; and Hirschhorn-Cymerman et al. (J Exp Med 2009; 206: 1103-1116) used OX86 together with cyclophosphamide in a mouse model as a potential chemoimmunotherapy. However, OX86 would not be expected to bind human OX40 and, when choosing an antibody that would be effective in humans, one would, in the light of the Weinberg work, choose an antibody that did bind at the OX40L-binding site.
In vivo ligation of the human CD134 receptor (by anti-human CD134-specific antibodies which interact with the OX40L binding domain on human CD134; US 2009/0214560 A1) in severe combined immunodeficient (SCID) mice enhances anti-tumour immunity, which leads to tumour growth inhibition of various human malignant tumour cell lines, e.g. lymphoma, prostate cancer, colon cancer, and breast cancer.
The exact mechanism of human CD134 ligation-mediated anti-tumour immune responses in humans is not yet elucidated, but is thought to be mediated via the CD134 transmembrane signalling pathway that is stimulated by the interaction with OX40L. This interaction is mediated by the binding of trimeric OX40L to CD134. In current anti-cancer therapies, the use of trimerized OX40 ligand is proposed as a more effective agent than anti-OX40 antibodies (Morris et al. Mol Immunol 2007; 44: 3112-3121).